Qi Ruochen, Zhang Weitao, Zheng Long, Xu Ming, Rong Ruiming, Zhu Tongyu, Yang Cheng
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Shanghai Medical College, Fudan University, Shanghai 200032, China.
Ann Transl Med. 2020 Mar;8(5):167. doi: 10.21037/atm.2020.02.12.
Renal fibrosis is the inevitable outcome of all progressive chronic kidney diseases (CKD) and leads to a gradual loss of renal function. We previously reported cyclic helix B peptide (CHBP), a novel synthesized peptide derived from erythropoietin, had shown effective renoprotection. In this study, we investigated the anti-fibrotic and renoprotective effect of CHBP in a murine renal tubulointerstitial fibrosis model induced by unilateral ureter obstruction (UUO).
Mice were subjected to the UUO model and CHBP was given intraperitoneally. To assess the therapeutic effects of CHBP, pathological injury, deposition of extracellular matrix (ECM) and the progression of epithelial-mesenchymal transition (EMT) were examined . The anti-fibrotic effects of CHBP was validated using TCMK-1 cells treated with TGF-β1. Involvement of the NLRP3 pathway was demonstrated both and .
CHBP significantly ameliorated renal tubulointerstitial injury and fibrosis in terms of ECM deposition. The EMT process was also alleviated after CHBP treatment. Similar therapeutic effects of CHBP were also observed in TGF-β1 treated tubular epithelial cells (TECs). NLRP3/caspase-1/IL-1β pathway was involved and activated upon injury, both and . While the activation of the NLRP3 pathway was found to be in negative correlation with CHBP treatment. CHBP could suppress the activation of NLRP3 and its downstream inflammatory mediators even with addition of extracellular ATP, a direct activator of the NLRP3 inflammasome.
Our results suggest that CHBP could effectively protect the kidney from renal tubulointerstitial fibrosis in the UUO model via counteracting the NLRP3/caspase-1/IL-1β pathway.
肾纤维化是所有进行性慢性肾脏病（CKD）的必然结果，并导致肾功能逐渐丧失。我们之前报道了一种新合成的源自促红细胞生成素的环状螺旋B肽（CHBP），它已显示出有效的肾脏保护作用。在本研究中，我们研究了CHBP在单侧输尿管梗阻（UUO）诱导的小鼠肾小管间质纤维化模型中的抗纤维化和肾脏保护作用。
将小鼠建立UUO模型并腹腔注射CHBP。为了评估CHBP的治疗效果，检测了病理损伤、细胞外基质（ECM）沉积以及上皮-间质转化（EMT）的进展情况。使用经转化生长因子-β1（TGF-β1）处理的TCMK-1细胞验证了CHBP的抗纤维化作用。同时证明了NLRP3通路的参与情况。
就ECM沉积而言，CHBP显著改善了肾小管间质损伤和纤维化。CHBP治疗后EMT过程也得到缓解。在TGF-β1处理的肾小管上皮细胞（TECs）中也观察到了CHBP类似的治疗效果。损伤时NLRP3/半胱天冬酶-1/白细胞介素-1β通路被激活并参与其中。而发现NLRP3通路的激活与CHBP治疗呈负相关。即使添加细胞外ATP（NLRP3炎性小体的直接激活剂），CHBP也能抑制NLRP3及其下游炎症介质的激活。
我们的结果表明，CHBP可通过对抗NLRP3/半胱天冬酶-1/白细胞介素-1β通路，有效保护UUO模型中的肾脏免受肾小管间质纤维化的影响。
